Attenuation of motor nerve terminal repetitive discharge by the 21-aminosteroid tirilazad: evidence of a neural calcium antagonist action.
Pretreatment with the 21-aminosteroid antioxidant compound tirilazad mesylate has been previously shown to retard the axotomy-induced anterograde degeneration of soleus motor nerve terminals in the cat. In the present study, we examined tirilazad's effects (7.7, 13.0 or 30.0 mg/kg twice daily P.O. for 6 days) on the excitability of normal cat soleus motor nerve terminals. Low frequency (0.4 Hz) neuromuscular transmission was measured as well as the occurrence of muscle contractile potentiation in response to either a 400 Hz/10 s episode of tetanic conditioning stimulation of the soleus nerve or the administration of a 200 microg/kg i.v. dose of the neuromuscular facilitatory drug edrophonium. The mechanism of the post-tetanic potentiation (PTP) or edrophonium-induced facilitatory response involves the occurrence of a stimulus-dependent repetitive discharge of the soleus motor nerve terminals due to an exaggeration of the nerve terminal Ca2+-mediated after-depolarization. Tirilazad pretreatment caused a dose-related suppression of PTP and the edrophonium response indicative of a suppression of motor nerve terminal repetitive discharge. These effects were not shared by 6 days of oral pretreatment of cats with a high dose combination of the antioxidants vitamin E (200 I.U./day) and selenium (50 microg/day). Thus, it is unlikely that the antioxidant properties of tirilazad are involved in the suppression of motor nerve terminal excitability. Rather, it is proposed that tirilazad suppresses delayed motor nerve terminal Ca2+ conductances secondary to its ability to decrease membrane phospholipid fluidity, and that this action might in some circumstances contribute to its neuroprotective activity.
Hall
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CNS Diseases Research, Pharmacia and Upjohn, Kalamazoo, MI 49001, USA. edward.d.hall@am.pnu.com
Yonkers
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D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002415:Cats; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000294:innervation*; D009411:Nerve Endings / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D011281:Pregnatrienes; C053355:tirilazad